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Largest GWAS Analysis to Date Offers Only Two New Candidate Genes

3 July 2009. Three papers appearing in this week's issue of Nature present the much anticipated results of genomewide association studies (GWAS) of schizophrenia, as well as meta-analyses of the three studies together. There are no break-out candidate genes, though there is support for previous linkage findings, several new candidates, as well as statistical modeling that supports the notion of genetic overlap between schizophrenia and bipolar disorder.

Perhaps surprisingly, none of the studies alone identified any genetic marker with significant association to the disease (by the commonly applied genomewide significance benchmark of p <5 x 10 -8). The meta-analyses pointed to three regions, particularly a large swath on the short arm of chromosome 6, which houses the major histocompatibility complex genes, among others. This complex region, fingered in linkage studies (see Lewis et al., 2003), has also been highlighted by various single candidate gene association studies (see SchizophreniaGene's Chromosome 6 compendium).

The lack of a large new crop of gene candidates is certain to rekindle the debate about the value of expensive large-scale GWAS versus other approaches (see below for historical notes), and while some observers will take these results as a failure of GWAS to deliver, Michael O'Donovan of Cardiff University in Wales, and coauthor of the International Schizophrenia Consortium paper, argues for a different interpretation. "Before today, you could count on the thumb of one hand the number of common variants that have been reliably identified in schizophrenia, so this is a significant increment in knowledge," he said at a press conference Wednesday at the World Conference of Science Journalism (WCSJ) in London. What is needed to follow up on these results is larger samples, O'Donovan argued. While this will be fairly expensive, "that's peanuts compared with the human and economic cost of ignorance about this disease," he said.

Daniel Weinberger of the National Institute of Mental Health, Bethesda, Maryland, sees it differently: “While we had hoped this brute force, clinically agnostic strategy would have been more fruitful, it is clear that the assumption of loading more cases on an already exhausted strategy is likely to only add a few more very small effect genes to the already too small list of very small effect genes," Weinberger wrote in an e-mail to SRF. "We have to critically consider the realistic possibility that the genetic and pathophysiologic heterogeneity of the condition we call schizophrenia may not be well suited for this strategy which assumes a quasi-unitary disease entity as part of its basic experimental logic.”

Although the three separate studies came to the same major conclusion about signals in the chromosome 6p21 region, they did report some different results. The study conducted by the SGENE consortium also found significant association in the combined sample near the neurogranin gene (NRGN) on 11q24.2 and for an intronic SNP in transcription factor 4 (TCF4) on 18q21.2.

And in their paper, the International Schizophrenia Consortium (ISC) deployed a modeling approach to try to estimate the number of genes involved in the disease. Their analysis, they report, supports the polygenic model of the disease whereby a common variation in many hundreds or even thousands of genes contributes to the disease, and also wherein a significant number of these are shared with bipolar disorder.

Difficult birth
In October 2005 (on the very weekend SRF was launched!), the World Congress on Psychiatric Genetics in Boston saw a contentious series of exchanges between the proponents of putting most of the genetic funding eggs into a couple of large GWAS baskets, on the one hand, and others who suggested a combination approach that also utilized smaller, multifaceted studies of candidate genes. These latter veterans of psychiatric genetics argued that their approaches had already yielded a considerable number of strong candidate genes found by fine-mapping positional candidate genes under linkage peaks, and they raised concerns that large GWAS would wash out signals at work in smaller populations.

The large-scale GWAS approach was ultimately selected by funders around the world, and great—and rapid—results were anticipated by many in the schizophrenia community. Thus, there was disappointment when the first round of reports failed to deliver either a few genes of large effect or many confirmed genes of small to medium effect (see SRF related news story; SRF news story; SRF related news story).

The first apparent success of the GWAS era was the suggestion that copy number variations (CNVs)—major disruptions in one or more genes in one or a few individuals—could account for schizophrenia in myriad different ways. However, not everyone agreed that this evidence was so clear, or that if it was a factor, that it accounted for a substantial percentage of schizophrenia risk. (see the lively discussion at SRF related news story; SRF news story; SRF related news story). Thus, the community was left anticipating the GWAS studies described in these papers, which looked at the contribution of common SNPs across the genome.

Combining datasets
In one of the papers in the current issue of Nature, the ISC, a multinational collaboration led by Pamela Sklar of the Broad Institute, Cambridge, Massachusetts, found no genes with genomewide significance in their sample of 3,322 cases and 3,587 controls of European origin. A similar result was obtained by the SGENE consortium (2,663 cases, 13,498 controls of European origin), led by Kari Stefansson of deCODE Genetics in Reykjavik, Iceland, and by the Molecular Genetics of Schizophrenia (MGS) study (European: 2,681 cases, 2,653 controls; African American: 1,286 cases, 973 controls), led by Pablo Gejman of NorthShore University HealthSystem and Northwestern University, Evanston, Illinois.

According to the papers, when the three groups combined the European samples of more than 8,000 cases and 19,000 controls, and applied varying methods of statistical analysis, their findings all converged on a swath at chromosome 6p21. Originally tagged as a region of interest more than 30 years ago (Smeraldi et al., 1976) and later supported by linkage studies (see Lewis et al., 2003), this stretch of DNA contains a host of major histocompatibility complex genes, coding for proteins involved in immune functions. This stretch also contains many other genes of other function (see Sanger Institute overview of chromosome 6).

The results on chromosome 6p21 might tantalize with the possibility of linking genetics to previous epidemiologic findings regarding schizophrenia and season of birth effects, autoimmune disease, and prenatal infection (see SRF related news story; SRF news story). However, as the Associated Press reported, Stefansson noted the presence of other, non-immune genes in this region, and warned, "It's guilt by association; it's not really a link."

Some different approaches and results
The ISC attempted to glean some information by combining the tens of thousands of markers that had even nominal (i.e., not statistically significant) association with the disease. With the understanding that this "polygenic score" would probably contain a vast majority of false positives, the statistics team led by Shaun Purcell of the Broad Institute nonetheless hoped it would allow them make some observations about the overall common genetic landscape of the disorder. In particular, they wanted to test whether the data supported the polygenic theory that hundreds or even thousands of genes can influence the risk of schizophrenia, notably advanced by Gottesman and Shields (1967). According to the authors, the resulting modeling, strongly supports "a polygenic basis to schizophrenia that 1) involves common SNPs, 2) explains at least one-third of the total variation in liability, 3) is substantially shared with bipolar disorder, and 4) is largely not shared with several non-psychiatric diseases."

The question of a genetic link between bipolar disorder and schizophrenia has been debated since the disease categories were created, and O'Donovan and colleagues at Cardiff University have applied a particular focus on this question (see SRF Live Discussion). Their research agenda was supported earlier this year by a large Swedish epidemiology study that left little doubt about the shared heritability of the disorders (see SRF related news story).

Outside the MHC regions, the SGENE group identified significant results in their meta-analyses for an SNP just upstream from the neurogranin gene (NRGN) on 11q24.2, coding for a synaptic protein, and an intronic SNP in transcription factor 4 (TCF4) on 18q21.2.

The MGS group's paper is notable in that it is the first report of an African American schizophrenia GWAS sample. Although none of the genes identified reached genomewide significance, it will be interesting to follow this line of research as researchers try to determine whether different SNPs and/or genes are at play in different populations.

Where to now?
If 8,000 subjects were not enough to identify more than a handful of markers indicating nearby schizophrenia risk loci (most of which were in a region already suspect), what would it take to find a substantial number of the many common variants presumably affecting disease risk? David Collier of the Institute of Psychiatry in London, and a member of the SGENE collaboration, told SRF at the WCSJ in London that he thought genomewide statistical significance might not begin to emerge until samples of 100,000 cases and more than 100,000 controls had been collected. He said that assembling such samples was a challenge, but not impossible, especially since groups like the Wellcome Trust are assembling large control samples to study a range of diseases.

Thus, the field is left with some important questions, beginning with, Is this the time for a course correction in regard to studying the role of common variants, i.e., to steer the ship away from massive GWAS samples and toward other approaches that incorporate endophenotypes (see SRF live discussion) or that attempt to tease apart the complex and varying phenotype of the disease itself (see SRF related news story)? Or is this the time for a steady hand on the GWAS ship's wheel—in for a penny, in for a pound, to mix some metaphors?

Furthermore, how much effort should be spent on probing the contribution of copy number variation, or on resequencing the many strong candidate genes already existing to find new common or rare variants? As Collier told SRF, GWAS of the type reported this week will explain only the risk due to common polymorphisms at the population level, which the ISC estimates at one-third or more of the contribution to the disease, though this number may be more or less. The remainder of genetic variation, said Collier, will come from some combination of CNVs and rare variants.

How best to probe gene effects that only emerge under the influence of variation in other genes (epistasis)? Are family studies going to yield more fruit than case-control studies? The schizophrenia community awaits a consensus response to these questions from the genetics community, and SRF invites readers to begin this discussion.—Hakon Heimer (with additional reporting by Peter Farley).

The International Schizophrenia Consortium; Manuscript preparation, Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P; Data analysis, Purcell Leader SM, Stone JL; GWAS analysis subgroup, Sullivan PF, Ruderfer DM, McQuillin A, Morris DW, O'Dushlaine CT, Corvin A, Holmans PA, O'Donovan MC, Sklar P; Polygene analyses subgroup, Wray NR, Macgregor S, Sklar P, Sullivan PF, O'Donovan MC, Visscher PM; Management committee, Gurling H, Blackwood DH, Corvin A, Craddock NJ, Gill M, Hultman CM, Kirov GK, Lichtenstein P, McQuillin A, Muir WJ, O'Donovan MC, Owen MJ, Pato CN, Purcell SM, Scolnick EM, St Clair D, Stone JL, Sullivan PF, Sklar Leader P; Cardiff University, O'Donovan MC, Kirov GK, Craddock NJ, Holmans PA, Williams NM, Georgieva L, Nikolov I, Norton N, Williams H, Toncheva D, Milanova V, Owen MJ; Karolinska Institutet/University of North Carolina at Chapel Hill, Hultman CM, Lichtenstein P, Thelander EF, Sullivan P; Trinity College Dublin, Morris DW, O'Dushlaine CT, Kenny E, Quinn EM, Gill M, Corvin A; University College London, McQuillin A, Choudhury K, Datta S, Pimm J, Thirumalai S, Puri V, Krasucki R, Lawrence J, Quested D, Bass N, Gurling H; University of Aberdeen, Crombie C, Fraser G, Leh Kuan S, Walker N, St Clair D; University of Edinburgh, Blackwood DH, Muir WJ, McGhee KA, Pickard B, Malloy P, Maclean AW, Van Beck M; Queensland Institute of Medical Research, Wray NR, Macgregor S, Visscher PM; University of Southern California, Pato MT, Medeiros H, Middleton F, Carvalho C, Morley C, Fanous A, Conti D, Knowles JA, Paz Ferreira C, Macedo A, Helena Azevedo M, Pato CN; Massachusetts General Hospital, Stone JL, Ruderfer DM, Kirby AN, Ferreira MA, Daly MJ, Purcell SM, Sklar P; Stanley Center for Psychiatric Research and Broad Institute of MIT and Harvard, Purcell SM, Stone JL, Chambert K, Ruderfer DM, Kuruvilla F, Gabriel SB, Ardlie K, Moran JL, Daly MJ, Scolnick EM, Sklar P. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009 Jul 1. Abstract

Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe'er I, Dudbridge F, Holmans PA, Whittemore AS, Mowry BJ, Olincy A, Amin F, Cloninger CR, Silverman JM, Buccola NG, Byerley WF, Black DW, Crowe RR, Oksenberg JR, Mirel DB, Kendler KS, Freedman R, Gejman PV. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. 2009 Jul 1. Abstract

Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, Werge T, Pietiläinen OP, Mors O, Mortensen PB, Sigurdsson E, Gustafsson O, Nyegaard M, Tuulio-Henriksson A, Ingason A, Hansen T, Suvisaari J, Lonnqvist J, Paunio T, Børglum AD, Hartmann A, Fink-Jensen A, Nordentoft M, Hougaard D, Norgaard-Pedersen B, Böttcher Y, Olesen J, Breuer R, Möller HJ, Giegling I, Rasmussen HB, Timm S, Mattheisen M, Bitter I, Réthelyi JM, Magnusdottir BB, Sigmundsson T, Olason P, Masson G, Gulcher JR, Haraldsson M, Fossdal R, Thorgeirsson TE, Thorsteinsdottir U, Ruggeri M, Tosato S, Franke B, Strengman E, Kiemeney LA, Group, Melle I, Djurovic S, Abramova L, Kaleda V, Sanjuan J, de Frutos R, Bramon E, Vassos E, Fraser G, Ettinger U, Picchioni M, Walker N, Toulopoulou T, Need AC, Ge D, Lim Yoon J, Shianna KV, Freimer NB, Cantor RM, Murray R, Kong A, Golimbet V, Carracedo A, Arango C, Costas J, Jönsson EG, Terenius L, Agartz I, Petursson H, Nöthen MM, Rietschel M, Matthews PM, Muglia P, Peltonen L, St Clair D, Goldstein DB, Stefansson K, Collier DA; Genetic Risk and Outcome in Psychosis (GROUP), Kahn RS, Linszen DH, van Os J, Wiersma D, Bruggeman R, Cahn W, de Haan L, Krabbendam L, Myin-Germeys I. Common variants conferring risk of schizophrenia. Nature. 2009 Jul 1. Abstract

Comments on News and Primary Papers
Comment by:  Todd LenczAnil Malhotra (SRF Advisor)
Submitted 3 July 2009 Posted 3 July 2009

The three companion papers published in Nature provide important new evidence for a role of the MHC complex and common variation across the genome in risk for schizophrenia. These studies have exploited the availability of comprehensive genotyping technologies, coupled with large cohorts of cases and controls, to identify candidate loci for disease susceptibility.

A notable feature of these papers is the clear willingness of each of the groups to share its data, and to provide overlapping presentations of each others’ results. The combination of datasets permitted the statistical significance of the MHC findings to emerge, thereby increasing confidence in results. The implication that immune processes may interact with genetic risk to influence schizophrenia risk is consistent with several lines of evidence, including our own small GWAS study (Lencz et al., 2007) implicating cytokine receptors in schizophrenia susceptibility.

Perhaps most intriguing is the finding from the International Schizophrenia Consortium demonstrating that a “score” test—combining...  Read more

View all comments by Todd Lencz
View all comments by Anil Malhotra

Comment by:  Daniel Weinberger, SRF Advisor
Submitted 3 July 2009 Posted 3 July 2009

The three Nature papers reporting GWAS results in a large sample of cases of schizophrenia and controls from around Western Europe and the U.S. are decidedly disappointing to those expecting this strategy to yield conclusive evidence of common variants predicting risk for schizophrenia. Why has this extensive and very costly effort not produced more impressive results? There are likely to be many explanations for this, involving the usual refrains about clinical and genetic heterogeneity, diagnostic imprecision, and technical limitations in the SNP chips. But the likely, more fundamental problem in psychiatric genetics involves the biologic complexity of the conditions themselves, which renders them especially poorly suited to the standard GWAS strategy. The GWA analytic model assumes fixed, predictable relationships between genetic risk and illness, but simple relationships between genetic risk and complex pathophysiological mechanisms are unlikely. Many biologic functions show non-linear relationships, and depending on the biologic context, more of a potential pathogenic...  Read more

View all comments by Daniel Weinberger

Comment by:  Irving Gottesman
Submitted 3 July 2009 Posted 3 July 2009
  I recommend the Primary Papers

The synthesis and extraction of the essence of the 3 Nature papers by Heimer and Farley represents science reporting at its best. Completion of the task while the ink was still wet shows that SRF is indeed in good hands. Congratulations on being concise, even-handed, non-judgmental, and challenging under the pressure of time.

View all comments by Irving Gottesman

Comment by:  Christopher RossRussell L. Margolis
Submitted 6 July 2009 Posted 6 July 2009

Schizophrenia Genetics: Glass Half Full?
While it may be disappointing that the GWAS described above did not identify more genes, they nevertheless represent a landmark in psychiatric genetics and suggest a dual approach for the future: continued large-scale genetic association studies along with alternative genetic approaches leading to the discovery of new genetic etiologies, and more functional investigations to identify pathways of pathogenesis—which may themselves suggest new etiologies.

The consistent identification of an association with the MHC locus reinforces (without proving, as pointed out in the SRF news story) long-standing interest in the involvement of infectious or immune factors in schizophrenia pathogenesis (Yolken and Torrey, 2008). Epidemiologic and neuropathological studies that include patients selected for the presence or absence of immunologic genetic risk variants could potentially clarify etiology; cell and mouse model studies could clarify pathogenesis (  Read more

View all comments by Christopher Ross
View all comments by Russell L. Margolis

Comment by:  David Collier
Submitted 6 July 2009 Posted 6 July 2009
  I recommend the Primary Papers

This report is unnecessarily negative, from my point of view. The three studies show not only that GWAS can identify susceptibility alleles for schizophrenia, but that the majority of risk comes from common variants of small effect. These can be found, but as in other complex traits and diseases, such as obesity and height, considerable power is needed, because effect sizes are small, meaning greater samples sizes. This approach works: there are now almost 60 variants influencing height (Hirschhorn et al., 2009; Soranzo et al., 2009; Sovio et al., 2009). Furthermore, the genes identified so far from both traditional mapping, CNV analysis and GWAS, point to two biological pathways, the integrity of the synapse (neurexin 1, neurogranin, etc.) and the wnt/GSK3β signaling pathway (DISC1, TCF4, etc.), which is involved in functions such as neurogenesis in the brain. The identification of disease pathways for schizophrenia has major...  Read more

View all comments by David Collier

Comment by:  Michael O'Donovan, SRF AdvisorNick CraddockMichael Owen (SRF Advisor)
Submitted 9 July 2009 Posted 9 July 2009

Some commentators in their reflections take a rather negative view on what has been achieved through the application of GWAS technology to schizophrenia and psychiatric disorders more generally. We strongly disagree with this position. Below, we give examples of a number of statements that can be made about the aetiology of schizophrenia and bipolar disorder that could not be made at high levels of confidence even two years ago that are based upon evidence deriving from the application of GWAS.

1. We know with confidence that the role of rare copy number variants in schizophrenia is not limited to 22q11DS (VCFS) (reviewed recently in O’Donovan et al., 2009). We do not yet know how much of a contribution, but we know the identity of an increasing number of these. Most span multiple genes so it may prove problematic as it has in 22q11DS to identify the relevant molecular mechanisms. However, for one locus, the CNVs are limited to a single gene: Neurexin1 (Kirov et al., 2008;   Read more

View all comments by Michael O'Donovan
View all comments by Nick Craddock
View all comments by Michael Owen

Comment by:  Kevin J. Mitchell
Submitted 9 July 2009 Posted 9 July 2009

GWAS Results: Is the Glass Half Full or 95 Percent Empty?
The publication of the latest schizophrenia GWAS papers represents the culmination of a tremendous amount of work and unprecedented cooperation among a large number of researchers, for which they should be applauded. In addition to the hope of finding new “schizophrenia genes,” GWAS have been described by some of the researchers involved as, more fundamentally, a stern test of the common variants hypothesis. Based on the meagre haul of common variants dredged up by these three studies and their forerunners, this hypothesis should clearly now be resoundingly rejected—at least in the form that suggests that there is a large, but not enormous, number of such variants, which individually have modest, but not minuscule, effects. There are no common variants of even modest effect.

However, Purcell and colleagues now argue for a model involving vast numbers of variants, each of almost negligible effect alone. The authors show that an aggregate score derived from the top 10-50 percent of a set of 74,000...  Read more

View all comments by Kevin J. Mitchell

Comment by:  David J. Porteous, SRF Advisor
Submitted 9 July 2009 Posted 10 July 2009
  I recommend the Primary Papers

Thumbs up or down on schizophrenia GWAS?
The triumvirate of schizophrenia GWAS studies just published in Nature gives cause for thought, and bears close scrutiny and reflection. To my reading, these three studies individually and collectively lead to an unambiguous conclusion—there is a lot of genetic heterogeneity and not one individual variant of common ancient origin accounts for a significant fraction of the genetic liability. To put it another way, there is no ApoE equivalent for schizophrenia. Strong past claims for ZNF804A and others look to have fallen by the statistical wayside. Putting the results of all three studies together does appear to provide support for a long known, pre-GWAS association with HLA, but otherwise it is hard to give a strong "thumbs up" to any specific result, not least because of the lack of replication between studies. The results are nevertheless important because the common disease, common variant model, on which GWAS are based and the associated cost justified, is strongly rejected as the main contributor to the genetic...  Read more

View all comments by David J. Porteous

Comment by:  Sagiv Shifman
Submitted 11 July 2009 Posted 11 July 2009

The main question that arises from the three large genomewide association studies published in Nature is, What should we do next?

One important way forward would be to follow up the association findings in the MHC region. We need to understand the biological mechanism underlying this association. If the association signal is indeed related to infectious diseases, this line of inquiry may lead to the highly desired development of a treatment that might prevent the diseases in some cases.

One possible explanation for the association between schizophrenia and the MHC region (6p22.1) is that infection during pregnancy leads to disturbances of fetal brain development and increases the risk of schizophrenia later in life. A possible test for the theory of infectious diseases as risk factors for schizophrenia would be to study the associated SNPs in 6p22.1 in fathers and mothers of subjects with schizophrenia relative to parents of control subjects. If the 6p22.11 region is related to the tendency of mothers to be infected by viruses during pregnancy, we would expect the SNPs...  Read more

View all comments by Sagiv Shifman

Comment by:  Alan BrownPaul Patterson
Submitted 17 July 2009 Posted 17 July 2009

The three companion papers in this week’s issue of Nature, in our view, support the case for investigating interaction between susceptibility genes and infectious exposures in schizophrenia. We and others have argued previously that genetic studies conducted in isolation from environmental factors, and studies of environmental influences in the absence of genetic data, are necessarily limited. Maternal influenza, rubella, toxoplasmosis, herpes simplex virus, and other infections have each been associated with an increased risk of schizophrenia, with effect sizes ranging from twofold to over fivefold. While these epidemiologic findings clearly require replication in independent cohorts, two new developments provide further support for the hypothesis. First, a growing number of animal studies of maternal immune activation have documented behavioral and brain phenotypes in offspring that are analogous to findings from clinical research in schizophrenia, and these findings are mediated in large part by specific cytokines (Meyer et al.,...  Read more

View all comments by Alan Brown
View all comments by Paul Patterson

Comment by:  Javier Costas
Submitted 17 July 2009 Posted 17 July 2009
  I recommend the Primary Papers

Two hundred years after Darwin’s birth and 150 years after the publication of On the Origin of Species, these three papers in Nature show the important role of natural selection in shaping the genetic architecture of schizophrenia susceptibility. If we compare the GWAS results for schizophrenia with those obtained for other diseases, it seems that there are less common risk alleles and/or lower effect sizes in schizophrenia than in many other complex diseases (see, for instance, the online catalog of published GWAS at NHGRI). This fact strongly suggests that negative selection limits the spread of susceptibility alleles, as expected due to the decreased fertility of schizophrenic patients.

Interestingly, the MHC region may be an exception. This region represents a classical example of balancing selection, i.e., the presence of several variants at a locus maintained in a population by positive natural selection (Hughes and Nei, 1988). In the case of the MHC, this...  Read more

View all comments by Javier Costas
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